One of the principal goals of modern organic chemistry is the development of new synthetic routes toward the controlled, efficient production of asymmetric compounds. Saturated carbon atoms, which constitute the backbone of most organic compounds, are attached to adjacent atoms through a tetrahedral arrangement of chemical bonds. If the four bonds are to different atoms or groups, the central carbon provides a chiral, or asymmetric center, and the compound therefore may have the ability to exist in two mirror-image, or enantiomeric forms. When synthetic organic chemists attempt preparation of these asymmetric compounds it is crucial to have a means to produce the desired enantiomer because compounds of the wrong enantiomeric form often lack the desired biological, physical or chemical properties. The present invention provides a new process for the synthesis of compounds in a desired enantiomeric form.
An attractive route to such optically active compounds is the enantioselective opening of meso-epoxides with nucleophiles. This procedure is highly efficient because it simultaneously establishes the absolute stereochemistry on two adjacent carbon atoms and results in a useful bifunctional product. An especially attractive version of these reactions involves the use of an enantioselective catalyst to control the position of attack by the nucleophile. In such cases a small amount of a chiral catalyst can be used to produce a large amount of enantiopure product. Prior to the Applicant's discovery, only three catalysts seem to have been reported which promote such reactions in highly enantioselective (&gt;90% enantiomeric excess) fashion. In two cases, the nucleophile is azide (Nugent, William, J. Am. Chem. Soc., 1992, 114, 2768; Martinez, Luis et al., J. Am. Chem. Soc., 1995, 117, 5897). In the remaining case, the nucleophile is t-butyl thiol (Iida, Takehiko et al., J. Am. Chem. Soc., 1997, 119, 4783). To the Applicant's knowledge, there have, however, been no reports of catalysts which promote the enantioselective addition of halides (e.g., Cl, Br, I) to meso-epoxides.
A general review of enantioselective ring opening of meso-epoxides is provided in Hodgson, D. M. Gibbs, A. R.: Lee G. P., Tetrahedron 1996, 52, 46, 14361. One report discloses the use of halodiisopinocamphenylboranes to prepare enantiopure halohydrins [Srebnik M.; Joshi. N. N.; Brown, H. C.; Israel J. of Chem. 1989, 29, 229]. This reaction however, is not catalytic but, rather. stoichiometric. Chiral trivalent aluminum compounds and aluminum chelates were also used to convert meso-epoxides to the chlorohydrin, but low enantiomeric excess was achieved in the stoichiometric process [Naruse, et al; Tetrahedron. 1988, 44, 15, 4747].
Clearly, there is a need to provide a catalytic process for the manufacture of optically active halohydrins as their trimethylsilyl esters. Other objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description which hereinafter follows.